We recently generated a mouse strain (OT-I/K14-OVAp) that exhibits a severe CD8 T cell dependent autoimmune disease. This grant application seeks to understand the essential tolerance failure that gives rise to this disease. The target of autoimmunity in this model is a self-antigen expressed in stratified epithelial tissue, including skin and esophagus. This tissue is monitored by specialized antigen presenting cells Langerhans Cells , that may invoke a different tolerance mechanism that self antigens from other tissues. The first aim tests the specific hypothesis that, in K14-OVAp mice, self-anti8gen is presented in a fully immunogenic form in the nodes, but that T cells become deleted or anergic as they continue to encounter antigen in parenchymal tissue. We further hypothesize that if antigen were also present in other tissues an abortive activation would dominate in the lymph nodes, due to presentation of antigen by tolerogenic interstitial DC. To test this concept, we will compare the T cell response that occurs in K14-OVAp mice to that which occurs in transgenic mice expressing the same antigen broadly in all tissues. By crossing these two mice we will determine if autoimmunity to an epithelial antigen can be controlled by ubiquitous antigen in other tissues. Built into our hypothesis is the notion that when presentation of self-antigen from stratified epithelial is not accompanied by presentation from other tissues, the health of the animal is more heavily dependent on parenchymal tolerance mechanisms. In this situation we imagine that stochastic factors, such as skin injury or the frequency of autoreactive cells might influence the balance between immunity and tolerance. To this end, we will determine the frequency of autoreactive T cells that correlates with disease. We will also use perforin or IFNg deficiency to test the hypothesis that CD8 T cell effector function in the skin results in immune escalation of disease.